Nuovi target, nuove insulineElisabetta Torlone

S.C. E.M.M.A.O. S. Maria della Misericordia Perugia

2

La dot.ssa Elisabetta Torlone dichiara di NON aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:

Dichiara altresì il proprio impegno ad astenersi, nell’ambito dell’evento, dalnominare, in qualsivoglia modo o forma, aziende farmaceutiche e/odenominazione commerciale e di non fare pubblicità di qualsiasi tiporelativamente a specifici prodotti di interesse sanitario (farmaci, strumenti,dispositivi medico-chirurgici, ecc.)

...

SAINT VINCENT DECLARATION10-12 OCTOBER 1989

.“Achieve a pregnancy outcome in thediabetic woman that approximates that of the non-diabetic woman.”

40 years laterCongenital malformations RR 5.0Perinatal mortality RR 3.7Preterm delivery RR 4.2Large for gestational age RR 4.5

51 WOMEN

Daily mean glucose values

71,9± 5,7mg/dl

Daily mean glucose values

78,3± 5,4mg/dl

Mean postprandial glucose peak/levels NEVER EXCEED 105,2 MG/DL

Grafico9

883.44.2

996.44.3

10105.87.1

12124.95.4

13136.33.7

14144.24.5

16164.65.6

18183.84.3

202043.9

21215.53.4

22226.14.1

24244.75.2

223.14.6

443.92.9

664.13.1

883.44.2

26 sett.

38 sett.

Ore

mg/dl

56.2

60.8

90.8

103.9

76.9

90.7

65.4

65.8

91.5

106.5

83.8

97.5

71.8

68.5

62.5

67.4

61.1

66.3

90.7

105.7

78.4

98.5

62.9

67.4

60.8

63.8

60.1

64.7

57.6

61

56.2

60.8

Foglio1

BASELINE (SETT. 12.2 2.4)

ORA8910121314161820212224246824H

CSII

MEDIA102.6116.7114.788.5131.2137.495.8115.593.4128.3125.9110.798.4100.2104.5102.6110.92

DS38.640.740.542.334.540.847.237.344.142.839.345.843.944.542.738.641.475

MDI

MEDIA100.2118.7111.7104.3123.5128.599.7105.8103.2119.9121.4100.2100.397.898.5100.2108.9133333333

DS24.221.528.424.325.722.324.624.127.421.826.222.828.429.727.524.225.26

pNSNSNS

Picco della Glicemia dopo pasto (CGMS): 69,4±23.9’

Glicemie Normali in Gravidanza

Hernandez T.L et al. Patterns of glycemia in normal pregnancy: should the current therapeutic targets be challenged? Diabetes Care; 34(7):1660-68, 2011Hernandez Teri L and Barbour Linda A. Review: A Standard Approach to Continuous Glucose Monitor Data in Pregnancy for the Study of Fetal Growth and Infant

Outcomes, Diabetes Technology & Therapeutics Volume 15, Number 2, 1-8, 2013

Una chetosi frequente e prolungata può avere effetti negativi sul feto e deve essere evitata durante la gravidanza; a questo scopo, devono essere effettuati controlli frequenti della chetonuria e/o chetonemia al risveglio, in caso di malattie intercorrenti, e comunque in presenza di valori glicemici persistentemente >180 mg/dl (Jovanovic L. Medical management ).

Il principale corpo chetonico aumentato nella chetoacidosi è il beta-OHB (beta-idrossibutirrato);né l’acetone né il beta-OHB reagiscono fortemente col nitroprussiato (reagente utilizzato per evidenziare la presenza di chetonuria) come l’acetoacetato, pertanto i livelli di chetoni plasmatici di una paziente possono essere sottostimati dalla sola misurazione della chetonuria.

Klocker e coll. hanno dimostrato che la misurazione del beta-OHBplasmatico rispetto a quella dell’acetoacetato urinario riduce i costi, ed è in grado di monitorare più precisamente la risoluzione della chetoacidosi (Klocker AA, 2013). Perciò il dosaggio dei chetoni plasmatici sarebbe da preferire a quello dei chetoni urinari (Gruppo interassociativo AMD-SIDSIEDP 2015). Le recenti linee-guida NICE sottolineano l’importanza di offrire il dosaggio della chetonemia alla donna con diabete tipo 1 sia in programmazione sia in gravidanza(NICE 2015; Dalfrà MG, 2015).

Monitoraggio dei Chetoni

Black: Early pregnancy (12-16 week)Grey: Late pregnancy (28-32 week)

….. the optimal timing for prandial insulin is 15 min before meals in early pregnancy

and 30–40 min before meals in late pregnancy.Black: Early pregnancyGrey: Late pregnancy

Postprandial Glucose Disposal Postprandial Insulin peak

Rapid-acting insulin

Time, h

Insu

lin A

ctio

n (A

t Mea

ltim

e)* From the normal pancreas

'Faster-acting' insulin

RHI

*Schematic representation.Home PD. Diabetes Obes Metab. 2015;17:1011-1020.

Ultra-Fast-Acting Insulin: Approaching a More Exact Physiological Insulin Profile

• First-generation rapid-acting insulins had improved action profile vs RHI

• Ultra-fast-acting insulins:– Better approach physiological insulin

secretion in T1DM– Replace early insulin secretion in T2DM– Have a better profile for pump therapy

Faster-Acting Insulin Aspart: A New Formulation of Insulin Aspart

a. Brange J, et al. Diabetes Care. 1990;13:923-954.b. Heise T, et al. Diabetes Obes Metab. 2015;17:682-688. Figure courtesy of Tim Heise, MD.

• Insulin aspart: reduced strength of the insulin dimer leading to fast absorption[a]

• Faster-acting insulin aspart is a new formulation of insulin aspart, which contains 2 excipients, nicotinamide and arginine[b]

• Nicotinamide acts as an absorption modifier; arginine acts as a stabilizing agent

• Both ingredients are "generally recognized as safe" by the FDA

• The excipients result in a stable formulation and faster initial absorption after SC injection

Insulin aspart

ThrLys

AspThr

Tyr Phe PheGly

ArgGlu

Gly

Cys

Val

Leu

Tyr

Leu

Ala

Glu

Val

Leu

HisSer

GlyCysLeuHisGlnAsnValPhe

Asn CysTyr

Asn

Glu

Leu

Gln

Tyr

LeuSer

CysIleSerThrCysCysGln

Glu

Val

Ile

GlyA1

A21

B1

B30B28

SS

SS

SS

Nicotinamide: absorption modifier

L-Arginine: added for stability

*statistically significant.(Faster-acting insulin aspart is approved in the US, Canada, EU, Australia [CSII only in the EU].)Reproduced from Heise T, et al. Clin Pharmacokinet. 2017;56:551-559.

Faster-Acting Insulin Apart Pooled Analysis: Onset and Offset of Insulin Exposure

Ratio (95% CI)

Cmax (pmol/L) 1.04 (1.00, 1.08)

AUCIAsp, 0-12h (pmol·h/L) 1.01 (0.98, 1.04)

AUCIAsp, 2-12h (pmol·h/L) 0.89 (0.85, 0.93)*Treatment Difference (95% CI)

t50%Cmax (min) -9.5 (-10.7, -8.3)*

tlate50%Cmax (min) -12.2 (-17.9, -6.5)*

Faster aspartInsulin aspart

0

50

100

150

200

250

300

Insu

lin a

spar

t ser

um c

onc.

(pm

ol/L

)

0 1 2 3 4

Time (h)

5 6 7 8

–10/–12 min

Insulin Fiasp During Pregnancy and Laction in Women With Pre-existing

Diabetes

NCT03770767

https://clinicaltrials.gov/ct2/show/study/NCT03770767

Study Description

Condition or disease Intervention/treatment Phase

Diabetes MellitusPregnancyComplications

Drug: Faster-acting Aspart insulin FiaspDrug: Control (insulin Novorapid or insulin Lispro)

Phase 4

Study DesignStudy Type : Interventional (Clinical Trial)

Estimated Enrollment : 200 participants

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Estimated Study Start Date : September 1, 2019

Estimated Study Completion Date : August 31, 2022

Arm and Intervention/treatment

Arm Intervention/treatment

Active Comparator: Intervention with insulin FiaspWomen randomized to insulin Fiasp

Drug: Faster-acting Aspart insulin FiaspRandomization to treatment with insulin Fiasp

Active Comparator: Control (insulin Novorapid or Lispro)Women randomized to usual rapid-acting insulin, i.e. insulin NovoRapid or insulin Lispro.

Drug: Control (insulin Novorapid or insulin Lispro)Randomization to usual treatment with insulin Novorapid or Lispro

Eligibility Criteria

Ages Eligible for Study: 18 Years to 45 Years (Adult)Sexes Eligible for Study: Female

Accepts Healthy Volunteers: No

CriteriaInclusion Criteria:•Duration of type 1 or type 2 diabetes ≥ 12 months at inclusion•Pregnant with an intrauterine singleton living fetus (8 to 13 completed gestational weeks) at inclusion confirmed by an ultrasound scanExclusion Criteria:•A diagnosis with severe mental or psychiatric barriers or a concurrent disease on the decision of the principal investigator•No proficiency in Danish to understand oral and written information

Primary Outcome MeasuresBirth weight standard deviation score [ Time Frame: At delivery ]

Offspring birth weight (measured as standard deviation score) adjusted for gestational age and gender

0,9-1,2 UI/kg/24 ore+ 30-50%

Insulin requirement displayed a peak in week 9, a nadir in week 16, a second peak in week 37. For the change in insulinrequirement the sharpest slope was observed from 16 to week 37.

A.Garcia-Petterson et al, Diabetologia 2009

Fabbisogno insulinico nel DM1 in gravidanza

BI: birth injury; DO: delayed ossification; FD: fetal death; FGR: fetal growth retardation; FN: fetal nephrotoxicity; LBW: large birth weight; LI: labor induction; M: macrosomia, NH: neonatal hypoglycaemia; PD: placental dysfunction; RD: respiratory distress; SA:

skeletal anomalies;

Maka S. Hedrington & Stephen N. Davis , 2017

ABBIAMO SDOGANATO GLI ANALOGHI?

.

DETEMIR vs NPH

Nessuna differenza nelle complicanze materno-fetali, minor rischio ipoglicemico, glicemia a digiuno significativamente inferiore, controllo glicemico simile

2001-2009

79% R+RF 49%

35

NPH, Neutral Protamine Hagedorn; SMBG, self-monitoring of blood glucose

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. ADA. Diabetes Care. 2015;38(suppl 1):S77-S79. Jovanovic L, et al. Mt Sinai J Med. 2009;76:269-280. Castorino K, Jovanovic L. Clin Chem. 2011;57:221-230.

Insulin option Pregnancy Category Notes

Basal (control of fasting/preprandial glucose)

NPH B

Detemir B

Glargine C Not formally studied in pregnancy, though frequently prescribed

Degludec C Not studied in pregnancy

Bolus (control of postprandial hyperglycemia)

Aspart, lispro B

Regular B

Glulisine C Not formally studied in pregnancy

Pump therapy with rapid-acting analogs

B

DEGLUDEC.

NN1250-4300 EXPECT

Study Type : Interventional (Clinical Trial)

Estimated Enrollment : 300 participants

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: None (Open Label)

Masking Description: Sponsor staff involved in the clinical trial is masked according to company standard procedures.

Primary Purpose: Treatment

Official Title: A Trial Comparing the Effect and Safety of Insulin Degludec Versus Insulin Detemir, Both in Combination With Insulin Aspart, in the Treatment of Pregnant Women With Type 1 Diabetes

Actual Study Start Date : November 22, 2017

Estimated Primary Completion Date : October 15, 2021

Estimated Study Completion Date : October 15, 2021

Arm and Intervention/treatment

Arm Intervention/treatment

Experimental: Insulin Degludec Insulin Degludeconce daily and Insulin Aspart 2-4 times daily

Drug: Insulin degludec Injection for subcutaneous (s.c., under the skin) use once daily. The total trial duration for subjects will be maximum 25 months

Drug: Insulin Aspart Injection for subcutaneous (s.c., under the skin) use 2-4 times daily with meals. The total trial duration for subjects will be maximum 25 months

Active Comparator: Insulin Determir Insulin Determironce daily or twice daily and Insulin Aspart 2-4 times daily

Drug: Insulin Aspart Injection for subcutaneous (s.c., under the skin) use 2-4 times daily with meals. The total trial duration for subjects will be maximum 25 months

Drug: Insulin detemir Injection for subcutaneous (s.c., under the skin) use, once daily or twice daily. The total trial duration for subjects will be maximum 25 months

Eligibility CriteriaAges Eligible for Study: 18 Years and older (Adult, Older Adult)

Sexes Eligible for Study: FemaleAccepts Healthy Volunteers: No

CriteriaInclusion Criteria: - Female, age at least 18 years at the time of signing informed consent -Diagnosed with type 1 diabetes mellitus for at least 1 year prior to the day of screening -Treated with multiple daily subcutaneous insulin injections or continuous subcutaneous insulin infusion (CSII) or inhaled insulin for at least 90 days prior to the day of screening - The subject is planning to become pregnant within 12 months from randomisation and

willing to undertake pre-pregnancy counselling or the subject is pregnant with an intrauterine singleton living foetus (gestational week 8 to 13 (+6 days)) without any observed anomalies at randomisation, confirmed by an ultrasound scan

- HbA1c at screening below or equal to 8.0% (64 mmol/mol) by central laboratory

Exclusion Criteria: - Treatment with any medication for the indication of diabetes or obesity other than stated in

the inclusion criteria within the past 90 days prior to the day of screening - Pregnant and having proteinuria as evaluated by urine protein-to-creatinine ratio above or

equal to 300 mg/g in urine sample measured at screening- Subject being treated or became pregnant with assistance of in vitro fertilisation or other

medical infertility treatment - Receipt of any concomitant medication contraindicated in pregnancy according to local label within 28 days before screening and between screening and randomisation for non-pregnant subjects and 28 days before conception and between conception and randomisation for pregnant subjects - Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or pharmacologically dilated fundoscopy performed within the past 90 days prior to randomisation for non-pregnant subjects or within 28 days prior to randomisation for pregnant subjects. - History of severe hyperemesis gravidarum (requiring hospitalization)

PI Name Site NumberSite

StatusEmanuela Orsi 301 ActiveMarina Scavini 302 Active

Elisabetta Torlone 303 ActiveFabio Broglio 304 Approved

Annunziata Lapolla 305 ActiveAngela Napoli 306 Active

NN1250-4300 EXPECT: ITALIA

Take Home Messages• Il corredo di farmaci oggi a nostra disposizione ci

permette di ottenere target glicemici più stringenti• Gli analoghi rapidi LisPro, Aspart e i lenti Datemir e

Glargina possono essere usati tranquillamente nelle gravidanze complicate da diabete: i dati su Glulisinasono ancora modesti ma le gravidanze registrate apparentemente non hanno dimostrato effetti negativi.

• Le stesse indicazioni sono applicabili anche ai biosimililari, e alle insuline concentrate LP U200 e GlaU300

• Le insuline ultrarapide potranno aiutarci a raggiungere più facilmente i target glicemici post-prandiali

• Attendiamo i risultati dello studio EXPECT

“Achieve a pregnancy outcome in thediabetic woman that approximates that of the non-diabetic woman.”

I Have a dream….

GRAZIE PER L’ATTENZIONE

Nuovi target, nuove insulineDiapositiva numero 2Diapositiva numero 3Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 13Diapositiva numero 14Ultra-Fast-Acting Insulin: Approaching a More Exact Physiological Insulin ProfileFaster-Acting Insulin Aspart: A New Formulation of Insulin Aspart Faster-Acting Insulin Apart Pooled Analysis: Onset and Offset of Insulin ExposureInsulin Fiasp During Pregnancy and Laction in Women With Pre-existing DiabetesDiapositiva numero 19Arm and Intervention/treatment  Eligibility CriteriaPrimary Outcome MeasuresDiapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 27Diapositiva numero 28Diapositiva numero 29Diapositiva numero 30Diapositiva numero 31Diapositiva numero 32Diapositiva numero 35Diapositiva numero 36NN1250-4300 EXPECT Arm and Intervention/treatment  Eligibility CriteriaDiapositiva numero 40Take Home MessagesDiapositiva numero 42Diapositiva numero 43